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EMBO J. 2014 Oct 1;33(19):2201-15. doi: 10.15252/embj.201488057. Epub 2014 Aug 6.

Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.

Author information

1
Massachusetts General Hospital Cancer Center and Harvard Medical School Laboratory of Molecular Oncology, Charlestown, MA, USA.
2
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
3
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
4
Massachusetts General Hospital Cancer Center and Harvard Medical School Laboratory of Molecular Oncology, Charlestown, MA, USA dyson@helix.mgh.harvard.edu.

Abstract

Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE).

KEYWORDS:

Nanos; Pumilio; pRb; post‐transcriptional gene regulation; stress response

PMID:
25100735
PMCID:
PMC4282507
DOI:
10.15252/embj.201488057
[Indexed for MEDLINE]
Free PMC Article

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